Preclinical Evaluation of 89Zr-Df-IAB22M2C PET as an Imaging Biomarker for the Development of the GUCY2C-CD3 Bispecific PF-07062119 as a T Cell Engaging Therapy

  • Mol Imaging Biol. 2021 Dec;23(6):941-951. doi: 10.1007/s11307-021-01621-0.
Kevin P Maresca  1 ,  Jianqing Chen  2 ,  Divya Mathur  2  3 ,  Anand Giddabasappa  2 ,  Adam Root  2  4 ,  Jatin Narula  2 ,  Lindsay King  2 ,  David Schaer  2 ,  Jonathan Golas  2  3 ,  Keith Kobylarz  2 ,  Edward Rosfjord  2  5 ,  Edmund Keliher  2 ,  Laigao Chen  2 ,  Sripad Ram  2 ,  Eve H Pickering  2 ,  James S Hardwick  2 ,  Paul A Rejto  2 ,  Amira Hussein  6 ,  Ohad Ilovich  6 ,  Kevin Staton  7  8 ,  Ian Wilson  9 ,  Timothy J McCarthy  2
Affiliations
  • 1. Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA. [email protected].
  • 2. Worldwide Research, Development & Medicine, Pfizer Inc, New York, USA.
  • 3. Regneron Pharmaceuticals, Tarrytown, NY, USA.
  • 4. Generate Biomedicines, Inc, Cambridge, MA, USA.
  • 5. Black Diamond Therapeutics, New York, NY, USA.
  • 6. Invicro, A Konica Minolta Company, New Haven, USA.
  • 7. Evergreen Theragnostics, Jersey City, NJ, USA.
  • 8. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 9. ImaginAb Inc., Inglewood, CA, USA.
PMID: 34143379 DOI: 10.1007/s11307-021-01621-0
Abstract

Purpose: A sensitive and specific imaging biomarker to monitor immune activation and quantify pharmacodynamic responses would be useful for development of immunomodulating anti-cancer agents. PF-07062119 is a T cell engaging bispecific antibody that binds to CD3 and guanylyl cyclase C, a protein that is over-expressed by colorectal cancers. Here, we used 89Zr-Df-IAB22M2C (89Zr-Df-Crefmirlimab), a human CD8-specific minibody to monitor CD8+ T cell infiltration into tumors by positron emission tomography. We investigated the ability of 89Zr-Df-IAB22M2C to track anti-tumor activity induced by PF-07062119 in a human CRC adoptive transfer mouse model (with injected activated/expanded human T cells), as well as the correlation of tumor radiotracer uptake with CD8+ immunohistochemical staining.

Procedures: NOD SCID gamma mice bearing human CRC LS1034 tumors were treated with four different doses of PF-07062119, or a non-targeted CD3 BsAb control, and imaged with 89Zr-Df-IAB22M2C PET at days 4 and 9. Following PET/CT imaging, mice were euthanized and dissected for ex vivo distribution analysis of 89Zr-Df-IAB22M2C in tissues on days 4 and 9, with additional data collected on day 6 (supplementary). Data were analyzed and reported as standard uptake value and %ID/g for in vivo imaging and ex vivo tissue distribution. In addition, tumor tissues were evaluated by immunohistochemistry for CD8+ T cells.

Results: The results demonstrated substantial mean uptake of 89Zr-Df-IAB22M2C (%ID/g) in PF-07062119-treated tumors, with significant increases in comparison to non-targeted BsAb-treated controls, as well as PF-07062119 dose-dependent responses over time of treatment. A moderate correlation was observed between tumor tissue radioactivity uptake and CD8+ cell density, demonstrating the value of the imaging agent for non-invasive assessment of intra-tumoral CD8+ T cells and the mechanism of action for PF-07062119.

Conclusion: Immune-imaging technologies for quantitative cellular measures would be a valuable biomarker in immunotherapeutic clinical development. We demonstrated a qualification of 89Zr-IAB22M2C PET to evaluate PD responses (mice) to a novel immunotherapeutic.

Keywords
89Zr-IAB22M2C PET imaging; CD8 T cell; GUCY2C bispecific antibody; Immuno-oncology.
Products